Psychotic disorders involve an impairment of mental functioning to the extent that it interferes grossly with an individual's ability to meet the ordinary demands of life, characterized generally by severe affective disturbance, profound introspection, and withdrawal from reality with failure to test and evaluate external reality adequately formation of delusions or hallucinations, and regression presenting the appearance of personality disintegration. Included in this grouping are the affective disorders, paranoid states and schizophrenias.
Psychotic disorders may be treated in some cases by the administration of a major tranquilizer, or neuroleptic such as 4-[4-(p-chlorophenyl)-4-hydroxy-piperidino]-4'-fluorobutyrophenone (hereinafter "haloperidol" or "HAL"). The precise mechanism of action of haloperidol has not been clearly established.
Haloperidol generally reaches a steady state blood level after approximately five days of daily dosage and intra-individual variation in blood concentration is limited. Large individual differences in such variables as absorption, distribution, metabolism and excretion, however, result in great inter-individual differences in concentrations at the same dose. These variables are known to be affected by concomitant administration of other drugs. Commonly used drugs that may affect neuroleptic blood concentrations include lithium, trihexyphenidyl, anticonvulsants, tricyclic and monoamine oxidase inhibitor antidepressants, oral contraceptives, and antacids.
The most often reported effect is for HAL concentrations to decrease with concurrent administration of anticonvulsant drugs such as carbamazepine or phenobarbitol. The exact mechanisms for this effect are not known, but the induction of metabolic enzymes may be the common pathway. A primary metabolite of HAL in humans is the reduced form, 4-(4-(4-chlorophenyl)-4-hydroxy-piperdinyl)-1-(4-fluorophenyl)-1-butanol, hereinafter hydroxy-haloperidol (OH-HAL). However, the actual mechanism for its production in vivo has not been proven. Other possibilities are that the drugs affect the absorption, distribution, metabolism or excretion of haloperidol.
The behavioral and physiological effects of haloperidol and other neuroleptics have been thought to be altered by the concurrent administration of a number of medications above and beyond any effect on blood concentrations. The primary example of this is lithium and the controversy that began with a report that a deleterious synergism may occur. Also, it has been reported that in the rat a synergism may occur between the haloperidol and ascorbic acid.
Retinoic acids, particularly the isomers isotretinoin (13-cis-retinoic acid) and tretinoin (13-trans-retinoic acid) are endogenously occurring acid metabolites of vitamin A that are also used clinically for the treatment of some skin diseases and experimentally for some cancers. Retinoic acids have been shown to induce changes in many cellular and extracellular components, and can partially replace vitamin A in some critical activities for growth and development. However, there have been no drug interactions reported for retinoic acids previously.
Isotretinoin is currently used for the oral treatment of cystic acne with a dose in the range of 1 to 2 mg/kg/day in two divided daily doses.
Basic science studies have noted that the retinoic acids may regulate the function of protein kinase C in a complex fashion. This kinase, in turn, has been demonstrated in high concentrations in the brain in specific areas including the pathways involved in dopaminergic activity (Worley, P. F., Baraban, J. M., Snyder, S. H., Heterogenous localization of protein kinase C in rat brain: autoradiographic analysis of phorbol ester receptor binding. J. Neuroscience, 1986, 6(1), 199-207). Biochemically, protein kinase C is integral to some second messenger systems mediating neuronal activity. In this fashion, retinoids may have an effect on specific brain activity including dopaminergic transmission and its putative roles in motor activity and psychotic illness (Meltzer, H. Y., Goode, D. J., Fang, V. S., et al. Dopamine and schizophrenia. Lancet, 1976, 2, 1142). It has been postulated, for instance, that abnormalities of this kinase-mediated second messenger function in dopaminergic response may be related to the pathophysiology of dyskinesias (Poiletman, R., and Goldschmidt, T. Treatments of tardive dyskinesia as viewed from a calcium ion perspective. The Psychiatric Forum Spring: 1-5, 1984).
Complex pharmacokinetic interactions of psychoactive drugs are known to occur (Gaultieri, C. T. and S. F. Powell: Psychoactive drug interactions. J. Clin. Psychiat., 1978, 39, 720-729). However it is not known in the prior art of any interactions of psychoactive medications with any retinoids.